The objectives of the REDS-III program are to ensure safe and effective blood banking and transfusion medicine practices through a comprehensive, multi-targeted strategy involving basic, translational, and clinical research to improve the benefits of transfusion while reducing its risks. Improving blood component safety and availability in the U.S. and internationally through the conduct of epidemiologic, survey, and laboratory studies is the cornerstone of the REDS program. Transfusion therapy is the most commonly employed, and, arguably, one of the least understood medical procedures in the U.S. affecting about five million recipients annually. This research program is not only critical to public health in the U.S. but also to countries struggling with the HIV epidemic where blood safety and availability are major concerns. The REDS-III program is comprised of one Data Coordinating Center (DCC), one Central Laboratory (CL), four domestic hubs, and three international collaborative programs involving U.S. investigators and investigators at international blood centers. The REDS-III program will target the following blood banking and transfusion medicine areas: donor targeted strategies; blood banking; transfusion practices in adult patients; and education and training.